EP2830672A1 - Dispositif médical présentant une surface comprenant un métal antimicrobien - Google Patents

Dispositif médical présentant une surface comprenant un métal antimicrobien

Info

Publication number
EP2830672A1
EP2830672A1 EP13709112.0A EP13709112A EP2830672A1 EP 2830672 A1 EP2830672 A1 EP 2830672A1 EP 13709112 A EP13709112 A EP 13709112A EP 2830672 A1 EP2830672 A1 EP 2830672A1
Authority
EP
European Patent Office
Prior art keywords
gallium
medical device
bismuth
compound
titanium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP13709112.0A
Other languages
German (de)
English (en)
Inventor
Anna Arvidsson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dentsply IH AB
Original Assignee
Dentsply IH AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dentsply IH AB filed Critical Dentsply IH AB
Priority to EP13709112.0A priority Critical patent/EP2830672A1/fr
Publication of EP2830672A1 publication Critical patent/EP2830672A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A61C8/0048—Connecting the upper structure to the implant, e.g. bridging bars
    • A61C8/005—Connecting devices for joining an upper structure with an implant member, e.g. spacers
    • A61C8/0051—Abutment monobloc with restoration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C13/00—Dental prostheses; Making same
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C13/00—Dental prostheses; Making same
    • A61C13/0003—Making bridge-work, inlays, implants or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A61C8/0012—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy
    • A61C8/0013—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy with a surface layer, coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A61C8/0012—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy
    • A61C8/0013—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy with a surface layer, coating
    • A61C8/0015—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy with a surface layer, coating being a conversion layer, e.g. oxide layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A61C8/0048—Connecting the upper structure to the implant, e.g. bridging bars
    • A61C8/005—Connecting devices for joining an upper structure with an implant member, e.g. spacers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/10—Inorganic materials
    • A61L29/106—Inorganic materials other than carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04C—ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT PUMPS
    • F04C2270/00—Control; Monitoring or safety arrangements
    • F04C2270/04—Force
    • F04C2270/042—Force radial
    • F04C2270/0421—Controlled or regulated

Definitions

  • the present invention relates to a medical device having a surface layer comprising an anti-microbial metal, and to methods of producing such a device.
  • biocompatibility is a crucial issue.
  • the risk for foreign body reaction, clot formation and infection, among many other things, must be addressed and minimized in order to avoid adverse effects, local as well as systemic, which may otherwise compromise the health of the patient and/or lead to failure of the device. This is particularly the case for permanent implants.
  • Dental implant systems are widely used for replacing damaged or lost natural teeth.
  • a dental fixture screw
  • screw usually made of titanium or a titanium alloy
  • An abutment structure is then attached to the fixture in order to build up a core for the part of the prosthetic tooth protruding from the bone tissue, through the soft gingival tissue and into the mouth of the patient.
  • the prosthesis or crown may finally be seated.
  • a strong attachment between the bone tissue and the implant is necessary.
  • implants intended for contact with soft tissue such as abutments which are to be partially located in the soft gingival tissue
  • the compatibility with soft tissue is vital for total implant functionality.
  • an abutment is partially or completely surrounded by gingival tissue. It is desirable that the gingival tissue should heal quickly and firmly around the implant, both for medical and aesthetic reasons.
  • a tight sealing between the oral mucosa and the dental implant serves as a barrier against the oral microbial environment and is crucial for implant success. This is especially important for patients with poor oral hygiene and/or inadequate bone or mucosal quality. Poor healing or poor attachment between the soft tissue and the implant increases the risk for infection and peri-implantitis, which may ultimately lead to bone resorption and failure of the implant.
  • Enhancement of new tissue formation may be achieved for example by various surface modifications and/or deposition of bioactive agents on the surface.
  • this and other objects are achieved by medical device intended for contact with living tissue, comprising a substrate having a surface layer comprising one or more compound(s) of a non-toxic post-transition metal.
  • the layer comprising one or more compound(s) of a non-toxic post- transition metal, e.g. gallium compound(s) may have an atomic concentration (at%) of post-transition metal, e.g. gallium and/or bismuth, of at least 5 at%.
  • the gallium concentration in said layer is at least 10 at%, for example at least 15 at%, e.g. at least 20 at%.
  • the content of the post-transition metal may be less than 5 %, for example at least 0.05 at%.
  • the layer may have a gallium content of up to 50 at%.
  • the compound of a non-toxic post- transition metal constitutes the major part of the layer.
  • a medical device surface having a layer incorporating a non-toxic post- transition metal such as gallium or bismuth has been shown to be effective against various bacterial strains, and was shown to inhibit biofilm formation in vitro.
  • the medical device according to the invention may also be effective against other microbes, such as fungi.
  • said living tissue is soft tissue.
  • said living tissue may be cartilage or bone tissue.
  • said one or more compound(s) of a non-toxic post-transition metal also comprises an additional metal, for example a biocompatible metal such as titanium.
  • a biocompatible metal such as titanium. Titanium is known to be well tolerated by living tissue, and has been used as an implant material for many years. By including a biocompatible metal, e.g. titanium, in the gallium- containing layer, a surface is obtained which is more similar to established implant surfaces and which is even more likely to be well tolerated by living tissue.
  • the surface layer may be a metallic layer.
  • the compound comprising a non-toxic post-transition metal may be a metallic compound.
  • the non-toxic post-transition metal is selected from bismuth and gallium.
  • the compound(s) of the non-toxic post-transition metal may be selected from bismuth compound(s) and gallium compound(s).
  • a galliunn compound may be selected from the group consisting of gallium-titanium oxide, gallium nitride, gallium-titanium nitride, gallium carbide, gallium selenide, and gallium sulphide, gallium chloride, gallium fluoride, gallium iodide, gallium oxalate, gallium phosphate, gallium maltolate, gallium acetate and gallium lactate.
  • a bismuth compound may be selected from the group consisting of bismuth-titanium, bismuth-titanium oxide, bismuth-titanium nitride, bismuth nitride, bismuth carbide, bismuth selenide, and bismuth sulphide, bismuth chloride, bismuth fluoride, bismuth iodide, bismuth oxalate, bismuth phosphate, bismuth maltolate, bismuth acetate and bismuth lactate.
  • bismuth-titanium bismuth-titanium oxide, bismuth-titanium nitride, bismuth nitride, bismuth carbide, bismuth selenide, and bismuth sulphide, bismuth chloride, bismuth fluoride, bismuth iodide, bismuth oxalate, bismuth phosphate, bismuth maltolate, bismuth acetate and bis
  • the compound of a non-toxic post-transition metal is a nitride of at least one non-toxic post-transition metal, such as gallium nitride or bismuth nitride, optionally also comprising titanium.
  • non-toxic post-transition metals such as gallium or bismuth are particularly useful in the present invention, in particular for dental implant applications, because such compounds may provide an aesthetically desirable surface layer, in particular with respect to color.
  • Such nitrides can be deposited using thin film deposition techniques.
  • the nitride of a non-toxic post-transition metal may be selected from the group consisting of gallium-titanium nitride, gallium nitride, bismuth-titanium nitride, bismuth nitride, and gallium-bismuth-titanium nitride.
  • the layer comprising a compound of a non-toxic post-transition metal may further comprise a salt of a non-toxic post- transition metal, e.g. a gallium salt or a bismuth salt.
  • the salt may be deposited onto the surface layer comprising the compound of a non-toxic post-transition metal.
  • a gallium salt or a bismuth salt may be deposited onto a first layer comprising a first gallium or bismuth compound.
  • a salt deposit may increase the release of antimicrobial post-transition metal from the surface early after contact with living tissue, thus temporarily further enhancing an antibacterial or antimicrobial effect of the layer.
  • the layer comprising the compound of a post-transition metal may have a thickness in the range of from 10 nm to 1 .5 ⁇ .
  • a layer of at least 10 nm may be sufficient to provide a desirable antibacterial effect, whereas thick layers of up to 1 ⁇ may be desirable for aesthetic reasons, having a color suitable for e.g. dental implants.
  • the layer comprising the compound of a non-toxic post-transition metal may be a homogeneous layer.
  • the layer may also be a non-porous layer.
  • a non-porous layer is typically less susceptible of bacterial growth and biofilm formation compared to a porous layer.
  • the substrate on which the layer comprising the at least one gallium compound is provided may comprise a metallic material, typically a
  • the substrate may comprise a ceramic material.
  • the substrate may comprise a polymeric material, or a composite material.
  • the medical device of the invention is typically an implant intended for long-term contact with, or implantation into, living tissue.
  • the medical device is an implant intended for implantation at least partially into soft tissue.
  • the medical device may be intended for short-term or prolonged contact with living tissue, typically soft tissue.
  • the medical device may be a dental implant, in particular a dental abutment.
  • the medical device may be a bone anchored hearing device.
  • the medical device may be an orthopaedic implant.
  • the medical device may be a stent.
  • the medical device may be a shunt.
  • the medical device may be a catheter adapted for insertion into a bodily cavity such as a blood vessel, the digestive tract or the urinary system.
  • the invention provides a method of producing a medical device as described herein, comprising
  • the compound of a non-toxic post-transition metal is a nitride of a non-toxic post-transition metal, such as a nitride of gallium and/or bismuth.
  • step b) involves simultaneously or sequentially applying a non-toxic post-transition metal and an additional metal or metal compound onto said surface.
  • the additional metal or metal compound may comprise titanium. Applying the post-transition metal, and optionally also an additional metal or metal compound, can be achieved using a thin film deposition technique.
  • a medical device as described above may be used for preventing biofilm formation and/or bacterial infection of a surrounding tissue, in particular soft tissue.
  • the medical device of the invention may be used for preventing bacterial infection of gingival tissue and/or periimplantitis.
  • Figure 1 is a side view of a medical device according to an
  • the medical device is a dental abutment.
  • Figure 2 illustrates in cross-section part of a medical device according to embodiments of the invention, showing a substrate material and a layer comprising a gallium compound.
  • a medical device having a surface layer comprising a compound of a post-transition metal, in particular a nontoxic, antimicrobial post-transition metal, such as gallium and/or bismuth provides very advantageous effects in terms of reduced risk of infection, improved tissue healing and/or aesthetic performance.
  • a titanium body having a surface coating incorporating gallium (Ga) can prevent the growth of bacteria on and around the surface and thus may be useful in preventing detrimental infection around e.g. a dental abutment implanted into the gingiva.
  • a titanium body having a surface coating incorporating bismuth (Bi) can prevent the growth of bacteria on and around the surface and thus may be useful in preventing detrimental infection around e.g. a dental abutment implanted into the gingiva.
  • a tissue contact surface of a surface of a medical device comprises a compound of a post-transition metal.
  • the post-transition metal is non-toxic to mammalian cells at the concentrations that have a lethal effect on bacterial cells.
  • post-transition metal generally refers to metal elements found in groups 13-16 and periods 3-6 of the periodic table. Usually, aluminium, gallium, indium, thallium, tin, lead, bismuth and polonium are regarded as post-transition metals. In contrast, transition metals are formed of group 3-12 elements. Germanium and antimony are considered not as post- transition metals, but metalloid elements.
  • Group 16 of the periodic table only contains one post-transition metal: polonium, which is toxic. Hence, in the present invention, post-transition metals of groups 13-15 and periods 3-6 are preferred.
  • the post-transition metal used is nontoxic.
  • non-toxic means that the substance (e.g. a
  • compound or element) in question does not damage mammalian cells at concentrations that have a lethal effect on bacterial cells.
  • post-transition metals examples include thallium (Tl), lead (Pb) and polonium (Po).
  • Other post-transitional metals e.g. indium (In) and tin (Sn)
  • Tl thallium
  • Pb lead
  • Po polonium
  • Other post-transitional metals e.g. indium (In) and tin (Sn)
  • the non-toxic post transition metal used in the present invention is typically non-toxic when present in elementary form, as metal ions, and/or as one of the exemplary compounds given herein. Furthermore, the post-transition metal used in the present invention typically has an antimicrobial or antibacterial effect. Post-transition metals that are considered to have some antimicrobial or antibacterial effect (including any oligodynamic effect) include at least gallium, tin, lead, and bismuth.
  • the invention may employ at least one non-toxic, antimicrobial post-transition metal, which is preferably selected from gallium and bismuth.
  • a gallium compound may be applied to a medical device as a surface layer.
  • a gallium compound could be incorporated into at least part of a body forming a medical device, such that at least one surface of the device comprises the gallium compound.
  • a bismuth compound may be applied to a medical device as a surface layer.
  • a bismuth compound could be incorporated into at least part of a body forming a medical device, such that at least one surface of the device comprises the bismuth compound.
  • Gallium has been used in medicine at least since the 1940's, primarily as a radioactive agent for medical imaging.
  • the antibacterial properties of gallium have been investigated in several studies. In Kaneko et al. (2007) it was established that gallium nitrate (Ga(NO3)3) inhibits growth of
  • Gallium acts by disrupting iron metabolism. It may be assumed that gallium is also effective against other microbes, e.g. fungi such as yeasts or moulds.
  • Bismuth is known to possess antibacterial activity. Bismuth compounds were formerly used to treat syphilis, and bismuth subsalicylate and bismuth subcitrate are currently used to treat peptic ulcers caused by Helicobacter pylori. The mechanism of action of this substance is still not well understood.
  • Bibrocathol is an organic bismuth-containing compound used to treat eye infections, and bismuth subsalicylate and bismuth subcarbonate are used as ingredients in antidiarrheal pharmaceuticals.
  • Directive 2007/47/ec defines a medical device as: "any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings".
  • only medical devices intended for contact with living tissue are considered, that is, any instrument, apparatus appliance, material or other article of physical character that is intended to be applied on, inserted into, implanted in or otherwise brought into contact with the body, a body part or an organ.
  • said body, body part or organ may be that of a human or animal, typically mammal, subject.
  • the medical device is intended for human subjects.
  • Medical devices included within the above definition are for example implants, catheters, shunts, tubes, stents, intrauterine devices, and prostheses.
  • the medical device may be a medical device intended for implantation into living tissue or for insertion into the body or a body part of a subject, including insertion into a bodily cavity.
  • the present medical device may be intended for short-term, prolonged or long-term contact with living tissue.
  • short-term is meant a duration of less than 24 hours, in accordance with definitions found in ISO 10993-1 for the biological evaluation of medical devices.
  • prolonged refers to a duration of from 24 hours up to 30 days.
  • long-term is meant a duration of more than 30 days.
  • the medical device of the invention may be a permanent implant, intended to remain for months, years, or even life-long in the body of a subject.
  • implant includes within its scope any device of which at least a part is intended to be implanted into the body of a vertebrate animal, in particular a mammal, such as a human. Implants may be used to replace anatomy and/or restore any function of the body. Generally, an implant is composed of one or several implant parts. For instance, a dental implant usually comprises a dental fixture coupled to secondary implant parts, such as an abutment and/or a restoration tooth. However, any device, such as a dental fixture, intended for implantation may alone be referred to as an implant even if other parts are to be connected thereto.
  • biocompatible a material which, upon contact with living tissue, does not as such elicit an adverse biological response (for example inflammation or other immunological reactions) of said tissue.
  • soft tissue is meant any tissue type, in particular mammalian tissue types, that is not bone or cartilage.
  • soft tissue for which the medical device is suitable include, but are not limited to, connective tissue, fibrous tissue, epithelial tissue, vascular tissue, muscular tissue, mucosa, gingiva, and skin.
  • the term "compound of a post-transition metal” refers to a chemical entity comprising at least one post-transition metal and at least one additional element.
  • Non-limiting examples of such compounds include oxides comprising post-transition metal, nitrides comprising post-transition metal, alloys of at least one post-transition metal, and salts comprising post- transition metal.
  • the compound may comprise two or more post-transition metals.
  • compound(s) of a post-transition metal is intended to also refer to compounds incorporating one or more other metals, in particular biocompatible metals such as titanium, in addition to the one or more post- transition metal(s).
  • gallium compound refers to a chemical entity comprising gallium and at least one additional element.
  • gallium compounds include gallium oxide, gallium nitride, and gallium salts.
  • the gallium and the at least one additional element may be joined by covalent bonding or ionic bonding.
  • gallium compound is intended to also include compounds incorporating other metals in addition to gallium, in particular titanium.
  • gallium- titanium oxides, gallium-titanium nitrides etc are included within the definition "gallium compound”.
  • bismuth compound refers to a chemical entity comprising bismuth and at least one additional element.
  • bismuth compounds include bismuth oxide, bismuth nitride, and bismuth salts.
  • the bismuth and the at least one additional element may be joined by covalent bonding or ionic bonding.
  • bismuth compound is intended to also include compounds incorporating other metals in addition to bismuth, in particular titanium.
  • bismuth-titanium oxides, bismuth - titanium nitrides etc are included within the definition "bismuth compound”.
  • metal compound refers to a compound which comprises at least one metal and which has one or more properties which are associated with metals, such as a metallic lustrous color.
  • a metallic compound may be formed of a metal and a non-metal, or of two or more metals.
  • a metallic compound need not comprise non-metallic elements, but may be formed of metallic elements only.
  • at least the following compounds are considered metallic compounds: gallium nitride, gallium-titanium nitride, gallium-titanium, gallium- bismuth-titanium, gallium-bismuth-titanium nitride, bismuth nitride , bismuth- titanium nitride, and bismuth-titanium.
  • homogeneous layer refers to a layer having a chemical composition that is uniform in all directions (three dimensions).
  • FIGS 1 and 2 illustrate an embodiment according to the present invention in which the medical device is a dental abutment.
  • the dental abutment 100 comprises a body of substrate material 102 coated with a layer 101 comprising a gallium compound.
  • the layer 101 forms the surface of the abutment intended to face and contact the gingival tissue after implantation.
  • the medical device of the invention may be made of any suitable biocompatible material, e.g. materials used for implantable devices.
  • the medical device comprises a substrate having a surface which comprises a compound of a post-transition metal, such as a gallium compound or a bismuth compound.
  • the substrate may for example be made of a
  • the substrate of the medical device may be made of a biocompatible ceramic, such as zirconia, titania, shape memory metal ceramics and combinations thereof.
  • the substrate is preferably made of a metallic material.
  • the native oxide layer of a titanium substrate mainly consists of titanium(IV) dioxide (T1O2) with minor amounts of T12O3, TiO and Ti 3 O 4 .
  • the medical device typically has a native metal oxide surface layer.
  • a native metal oxide layer may, in turn, be covered by a thin film comprising the gallium compound.
  • a native metal oxide layer may be modified or replaced with a modified surface layer incorporating a post-transition metal, such as gallium or bismuth, for example a titanium- gallium oxide or titanium-bismuth oxide layer.
  • the medical device in particular the substrate, may be made of a biocompatible polymer, typically selected from the group consisting of polyether ether ketone (PEEK), poly methyl methacrylate (PMMA), poly lactic acid (PLLA) and polyglycolic acid (PGA) and any combinations and copolymers thereof.
  • PEEK polyether ether ketone
  • PMMA poly methyl methacrylate
  • PLLA poly lactic acid
  • PGA polyglycolic acid
  • the medical device is intended for short-term, prolonged or long-term contact with living tissue.
  • the medical device of the invention may be an implant, typically intended to temporarily or permanently replace or restore a function or structure of the body.
  • the medical device is intended for contact with soft tissue, and at least part of this soft tissue contact surface has a layer comprising a compound of a post-transition metal, e.g. a gallium compound or a bismuth compound.
  • the medical device may be an implant intended for contact primarily or exclusively with soft tissue, for example a dental abutment.
  • the medical device may be an implant to be inserted partially in bone and partially in soft tissue. Examples of such implants include one-piece dental implants and bone-anchored hearing devices (also referred to as bone anchored hearing aids).
  • the layer comprising the compound of a post-transition metal e.g. gallium or bismuth compound, is provided at least on a part of a soft tissue contact surface.
  • the medical device may also be suitable for contact with cartilage.
  • the medical device may be intended for contact with bone tissue, e.g. the jawbone, the femur or the skull of a mammal, in particular a human.
  • bone tissue e.g. the jawbone, the femur or the skull of a mammal, in particular a human.
  • Examples of such medical devices include dental fixtures and orthopedic implants.
  • the compound of a post-transition metal may be a gallium compound and/or a bismuth compound.
  • Suitable compounds include in particular compounds that can be applied on a surface using a thin film deposition technique.
  • gallium compounds include gallium oxide, gallium nitride, gallium carbide, gallium selenide, gallium sulphide, and other gallium salts that can be deposited using a thin film deposition, for example gallium chloride, gallium fluoride, gallium iodide, gallium oxalate, gallium phosphate, gallium maltolate, gallium acetate and gallium lactate.
  • the gallium compound comprises at least gallium oxide (Ga 2 Os).
  • Gallium oxide may be present in amorphous or crystalline form. Crystalline forms of gallium oxide include a-Ga 2 O3, -Ga 2 O3, y-Ga2O3, 5-Ga2O3, and s-Ga2O3.
  • suitable bismuth compounds include bismuth oxide, bismuth nitride, bismuth carbide, bismuth selenide, bismuth sulphide, and other bismuth salts that can be deposited using a thin film deposition, for example bismuth chloride, bismuth fluoride, bismuth iodide, bismuth oxalate, bismuth phosphate, bismuth maltolate, bismuth acetate and bismuth lactate.
  • the compound of a post-transition metal may optionally include at least one further metal, such as titanium.
  • a gallium compound may be selected from the group consisting of gallium oxide, gallium-titanium oxide, gallium nitride, gallium-titanium nitride, gallium- titanium, gallium-bismuth-titanium, and gallium-bismuth-titanium nitride.
  • a bismuth compound may be selected from the group consisting of bismuth oxide, bismuth-titanium oxide, bismuth nitride , bismuth-titanium nitride, bismuth-titanium, bismuth-gallium-titanium, bismuth-gallium-titanium- oxide, and bismuth-gallium-titanium nitride.
  • a layer of for example gallium oxide or gallium nitride exhibits slow, sustained release of gallium ions. Such release may be slower and more sustained compared to the release of gallium ions from a precipitated gallium salt, and may thus provide a more long-term effect with respect to biofilm formation.
  • a surface layer deposited using a thin film deposition method as used in embodiments of the invention firmly adheres to the underlying substrate and thus avoids problem related to peeling and flaking of the surface layer. Peeling and flaking may give rise to adverse inflammatory response of the surrounding tissue, and in addition may undermine the biofilm prevention effect of the surface layer.
  • release properties may be desirable. For example, a higher release rate of
  • antimicrobial post-transistion metal may be more favorable for short term use, i.e. for a medical device intended for short-term contact with living tissue, compared to a device intended for prolonged or long-term contact.
  • the release rate may be affected by various factors, for example the crystallinity of the compound.
  • the medical device may additionally comprise a salt of a post-transition metal, e.g. a gallium salt selected from the group consisting of gallium acetate, gallium carbonate, gallium chloride, gallium citrate, gallium fluoride, gallium formate, gallium iodide, gallium lactate, gallium maltolate, gallium nitrate, gallium oxalate, gallium phosphate, and gallium sulphate.
  • the salt may be a bismuth salt of formed of any of these counterions.
  • Such a salt may be provided as a deposit, e.g. precipitated, on the layer comprising the
  • the compound of a post-transition metal e.g. gallium compound or bismuth compound
  • the compound, optionally including a further metal such as titanium, may constitute the major part of said layer.
  • the atomic concentration (at%) of the elements together forming the compound of a post-transition metal constitute at least 50 at% of the layer, preferably at least 70 at% and more preferably at least 80 at% of the elements of the layer.
  • the atomic concentration of post-transition metal, e.g. gallium, in the layer may be in the range of from 5 at% up to 50 at%, for example at least 10 at%, at least 15 at%, at least 20 at%, at least 35 at% or at least 30 at%, and up to for example 50 at%, such as up to 45 at%, or up to 40 at%.
  • the atomic content of the post- transition metal may be less than 5 at%.
  • the atomic content of the post-transition metal may be in the range of from 0.01 to 20 at%, e.g. from 0.05 to 15 at%, such as from 0.1 to 15 at%.
  • the content of gallium in the layer may be at least 0.05 at% or at least 0.1 at%, for example at least 0.3 at% or at least 0.5 at%.
  • the compound of post-transition metal comprises bismuth
  • the content of bismuth in the layer may be for instance at least 0.1 at%, at least 0.2 at%, for example at least 1 at% or at least 1 .5 at%.
  • gallium compound is substantially pure gallium oxide
  • gallium (Ga2Os), the maximum content of gallium in the layer is 40 at%, and the maximum content of oxygen in the layer is 60 at%. However, impurities and contamination, for example carbon, may be present at up to 20 at%. If the gallium compound is gallium-titanium oxide, part of the gallium is replaced with titanium and so the total content of gallium and titanium would be 40 at%.
  • the gallium compound is substantially pure gallium nitride (GaN)
  • the maximum content of gallium in the layer is 50 at%
  • the maximum content of nitrogen is 50 at%. Contaminations may be present as described above. If part of the gallium is replaced with another metal, such as titanium, the total content of gallium and said other metal may still be 50 at%, or it may be higher, e.g. up to 75 %, if the nitrogen content is low.
  • the layer may contain 50 at% nitrogen, 25 at% titanium and 25 at% gallium.
  • the atomic concentration may be measured for example to a depth of 40 nm or less, and preferably not more than the layer thickness.
  • the atomic concentration can be measured using X-ray photoelectron spectroscopy (XPS).
  • post- transition metal such as gallium or bismuth
  • some post- transition metal may be released from the surface of the medical device over time.
  • the content of post-transition metal and possibly also of other materials present on the surface of the medical device may change over time.
  • the layer may in addition to the compound of a post-transition metal include one or more other elements or compounds (a dopant), for example at a content of 10 at% or less, as will be described in more detail below.
  • the layer comprising the gallium compound or other compound of a post-transition metal may also contain impurities or
  • contamination for example carbon
  • contamination typically in an amount of 20 at% or less, and preferably 15 at% or less, or 10 at% or less.
  • contamination may originate from the packaging.
  • wet packaging in which the surface may be protected by water, ethanol or the like, reduces the amount of contamination by carbon, compared to dry packaging where the surface is exposed to air which normally contains volatile hydrocarbons.
  • Contamination may also be present on the surface of the substrate before the layer comprising the gallium compound is applied.
  • the level of contamination typically represented by the atomic concentration of carbon, may be reduced by cleaning the surface before applying the compound of post-transition metal, and optionally after applying the compound of post-transition metal and/or by avoiding further contaminating the surface before measuring the atomic concentration of elements on the surface.
  • Table 1 summarizes possible atomic concentration ranges for a layer comprising bismuth nitride, bismuth-titanium nitride, gallium oxide, gallium- titanium oxide, gallium nitride or gallium-titanium nitride, respectively.
  • Table 1 Exemplary atomic concentrations of various elements of a gallium compound.
  • the compound of a post-transition metal may primarily comprise a post-transition metal and an additional metal, such as titanium.
  • the surface layer may comprise titanium- gallium or titanium-bismuth as the compound of a post-transition metal.
  • the content of post-transition metal may be in the range of from 0.01 to 20 at%, e.g. from 0.05 to 15 at%, such as from 0.1 to 15 at%, as described above.
  • the titanium content may be in the range of from 10 to 99.9 at%, e.g. 10 to 60 at%, or 10 to 30 at%.
  • the layer may additionally contain nitrogen at a content of from 0 to 15 at%.
  • the nitrogen content of the layer may typically be in the range of from 0 to 5 at%.
  • the layer may additionally have a relatively high but superficial oxygen content, e.g. from 0 up to about 60 at%.
  • the surface layer consists essentially of one or more of the compound(s) of a post-transition metal mentioned above.
  • “consists essentially of " here means that the layer contains little or no other material (dopants, contaminants, etc) except the one or more compound(s) of a post-transition metal, only for example up to 10 at%, preferably up to 5 at%, more preferably up to 2 at% and even more preferably up to 1 at% of other material.
  • the layer comprising the compound of a post-transition metal e.g. a gallium compound or bismuth compound
  • a post-transition metal e.g. a gallium compound or bismuth compound
  • carrier material such as polymers, solvents, etc.
  • the layer comprising the compound of a post-transition metal such as a gallium compound or a bismuth compound may have a thickness in the range of from 1 nm to 1 .5 ⁇ , for example 0.1 to 1 ⁇ , in particular from 0.3 to 1 ⁇ .
  • a layer having a thickness of at least 1 nm may provide sufficient antimicrobial effect.
  • Increasing layer thickness may provide a whiter color, which may be desirable for dental applications.
  • a layer having a thickness of from about 10 nm may be more aesthetically advantageous than present commercial dental abutments.
  • a gallium oxide layer of 40 nm has a deep bronze color which would be less visible through a patient's gingiva than current grey-metallic titanium abutments.
  • the layer containing the compound of a post-transition metal may optionally have a thickness of from 10 to 100 nm, or optionally up to 300 nm.
  • a layer thickness in the range of from 0.5 to 1 .5 ⁇ , e.g. from 0.7 to 1 .5 ⁇ or from 0.7 to 1 ⁇ may be preferred.
  • thinner layers may provide an acceptable color appearance and which at least may be more advantageous than prior art dental abutments.
  • the layer may be a dense layer, i.e. a non-porous layer.
  • the surface of the medical device may comprise a single layer.
  • the medical device may comprise multiple layers, at least one comprising a compound of a post-transition metal such as a gallium compound or a bismuth compound.
  • a salt of non-toxic post-transition metal may be provided on at least a portion of a thin-film deposited layer comprising the above-mentioned compound of non-toxic post-transition metal.
  • a solution of at least one gallium salt may be applied onto a thin-film deposited layer of a compound of post- transition metal, and allowed to evaporate.
  • Such embodiments may provide a high initial release of gallium upon contact with living tissue, which may be advantageous in many instances, for short-term, prolonged as well as for long-term tissue contact.
  • a surface layer of the medical device may contain at least one additional element(s) or compound(s), for example a bioactive element or compound that may further enhance tissue healing or function.
  • additional element(s) or compound(s) for example a bioactive element or compound that may further enhance tissue healing or function.
  • Such elements or compounds may be included as a dopant in the layer comprising the compound of a post-transition metal, typically at a content of 10 at% or less.
  • element(s) or compound(s) may be applied as a separate layer, e.g. on the layer comprising the compound of a post-transition metal.
  • the substrate may have a rough surface on which a layer comprising the compound of a post-transition metal is arranged. Since the layer comprising the compound of a post-transition metal may be thin, e.g. 100 nm or less, it may have good conformal step coverage, meaning that the layer follows the underlying surface roughness and substantially preserves it, without making it smoother. However, in embodiments where the layer comprising the compound of a post-transition metal is relatively thick, it may reduce the roughness of the underlying substrate surface.
  • the substrate surface roughness, and hence optionally also the surface of the medical device formed by the layer comprising the gallium compound of a post-transition metal, may have an average surface
  • a layer comprising a compound of a post-transition metal e.g. a gallium compound or a bismuth compounds as described herein may be particularly advantageous for medical devices having a surface roughness of at least 0.2 ⁇ , and may be increasingly useful for preventing biofilm formation on medical devices having even higher surface roughness.
  • a dental abutment comprising a titanium substrate may have a surface roughness of about 0.2- 0.3 ⁇ .
  • a gallium compound having a thickness of about 40 nm may substantially preserve this surface roughness (which may be desirable e.g. in order to facilitate a firm anchorage of the implant in the surrounding tissue) but may prevent biofilm formation on the implant surface and hence reduce the risk for infection and periimplantitis.
  • the layer comprising a compound of a post-transition metal may be formed by applying the compound of a post-transition metal onto the surface of a medical device, to form a surface layer.
  • the compound of a post- transition metal may be applied using known deposition techniques, especially thin film deposition techniques. Suitable techniques may include physical deposition, chemical deposition and physical-chemical deposition. One example of such techniques is atomic layer deposition (ALD) which can be used to provide e.g. a gallium oxide layer on a substrate surface
  • ALD atomic layer deposition
  • Physical deposition, chemical deposition, and physical-chemical deposition techniques may also be used for incorporating additional element(s) into a layer of compound(s) of post-transition metal, e.g. as dopants, in order to enhance healing or regeneration of the tissue contacting the medical device.
  • additional element(s) e.g. as dopants
  • ALD and other thin film deposition techniques are associated with several advantages for the deposition of the compound(s) of a post-transition metal, such as controlled layer thickness, controlled composition, high purity, conformal step coverage, good uniformity (resulting in a homogeneous layer), and good adhesion.
  • PVD may provide dense layers with excellent adhesion to the underlying substrate.
  • Example 1A Production of gallium oxide coated specimens
  • Example 1B Surface characterization of gallium oxide coated specimens
  • Ga 2 O3 coated specimens were oxygen (O), gallium (Ga), and titanium (Ti).
  • Ga concentrations varied between 4 to 9 atomic % (at%), as measured with acceleration voltages at 30 kV and 10 kV, respectively.
  • the analytical depth with this technique is estimated to be approximately 1 ⁇ , i.e. much deeper than the layer thickness. No differences in terms of surface morphology could be detected between commercially pure titanium controls and the Ga 2 O3 coated titanium.
  • XPS X-ray photoelectron spectroscopy
  • the contact angle was measured using a contact angle measuring system (Drop Shape Analysis System DSA 100, Kruss GmbH, Germany). Measurements were performed with deionized water. The results indicate that all specimens were hydrophobic (>90°), see Table 4.
  • Example 1C Antimicrobial effect of gallium oxide-coated surfaces It was found that a titanium body having a surface comprising gallium (Ga) in the form gallium oxide can prevent the growth of Pseudomonas aeruginosa and Staphylococcus aureus on and around a surface and thus may be useful in preventing detrimental infection around e.g. a dental abutment implanted into the gingiva. a) Inhibition of bacterial growth on streak plate
  • a film contact method (Yasuyuki et al, 2010) was used. Streak plates of Pseudomonas aeruginosa (PA01 ) or methillicin resistant Staphylococcus aureus (MRSA) were made and 1 colony was inoculated to 5 ml tryptic soy broth (TSB) in culture tubes and grown under shaking conditions for 18 hours. Cell density was measured in a
  • spectrophotometer at OD 600 nm and counted using a cell counting chamber.
  • the cell culture was adjusted with sterile TSB to 1 -5 X 10 6 cells/ml.
  • Specimens of commercially pure (cp) titanium coins (0 6.25 mm), cp titanium coins with a gallium oxide coating, or cp titanium coins with a commercially available titanium nitride (TiN) coating were aseptically prepared and put in respective well of a 12 well plate. Thin transparent plastic film was punched, and sterilized using 70 % ethanol and UV irradiation on each side. A 15 ⁇ drop of bacteria in TSB was applied on each specimen. One thin plastic film per specimen was placed over the bacteria on the specimens so that the bacterial solution was evenly spread over the specimen surface, ensuring good contact. After incubation for 24 hours at 30 ⁇ 1 °C, the film of each specimen was aseptically removed and washed by pipetting 1 ml PBS over the surface into a separate 2 ml eppendorf tube per specimen. The
  • Specimens of commercially pure (cp) titanium coins (0 6.25 mm), cp titanium coins with a gallium oxide coating, or cp titanium coins with a titanium nitride (TiN) coating were aseptically prepared and applied onto the biofilm. The antibacterial activity was analyzed in situ using the Live/Dead® stain.
  • Example 2A Production of nitride or metal coated specimens
  • Coins of commercially pure (cp) titanium (grade 4) were manufactured and cleaned before deposition of a 0.5-1 ⁇ thick layer of either titanium bismuth (TiBi), titanium nitride with bismuth (TiNBi), titanium gallium (TiGa) or titanium nitride with gallium (TiNGa) using physical vapor deposition (PVD).
  • TiBi titanium bismuth
  • TiNBi titanium nitride with bismuth
  • TiGa titanium gallium
  • TiNGa titanium nitride with gallium
  • PVD physical vapor deposition
  • Targets of TiBi and TiGa were used for TiBi/TiNBi and TiGa/TiNGa, respectively.
  • the specimens were thereafter packaged in plastic containers, and sterilized with electron beam irradiation.
  • Example 2B Surface characterization of nitride or metal coated specimens
  • TiNGa, TiNBi nitride specimens
  • TiNGa, TiNBi nitride specimens
  • a BiN or a GaN surface layer would have a goldish appearance as well.
  • the TiBi and TiGa specimens had a grey-metallic color, similar to that of the uncoated titanium specimens.
  • the surface roughness of specimens produced according to Example 2A was measured with surface profilometry (Hommel T1000 wave,
  • Example 2A In order to investigate the wettability of specimens produced according to Example 2A, the contact angle was measured using a contact angle measuring system (Drop Shape Analysis System DSA 100, Kruss GmbH, Germany). Measurements were performed with deionized water. The result showed that all specimens were hydrophilic ( ⁇ 90°) although variations between test specimens were observed, see Table 9.
  • Example 2C Release of gallium and bismuth from surface coatings Release of gallium (Ga) or bismuth (Bi) from all surface coatings (TiBi, TiNBi, TiGa, TiNGa) was confirmed in experiments. At a pH of 7.4 low amounts of Ga and Bi, respectively, were released, but at pH 5.0 the release of Bi increased significantly.
  • Example 2D Antimicrobial effect of nitride or metal coated specimens It was found that a titanium body having a surface comprising gallium (Ga) or bismuth (Bi) in the form TiGa, TiNGa, TiBi or TiNBi can prevent the growth of Pseudomonas aeruginosa and Staphylococcus aureus on a surface and thus may be useful in preventing detrimental infection around e.g. a dental abutment implanted into the gingiva. a) Antimicrobial effect of bismuth (Bi) and gallium (Ga) against
  • MRSA and PA01 were grown on Tryptic Soy agar (TSA) plates and S. sanguinis on horse blood plates for up to 24 hours whereas P. gingivalis was grown between 4 and 5 days on Fastidious Anaerobic agar (FAA) plates.
  • TSA Tryptic Soy agar
  • S. sanguinis S. sanguinis
  • P. gingivalis was grown between 4 and 5 days on Fastidious Anaerobic agar (FAA) plates.
  • FSA Fastidious Anaerobic agar
  • Fivefold dilution in at least five steps of gallium nitrate (Ga(NOs)3) or bismuth chloride (B1CI3) was done.
  • Bismuth salt had to be suspended in DMSO in order to enable salt to dissolve in culture media.
  • Equal amounts of bacterial solution and antimicrobial salt (in fivefold dilution) were mixed and incubated at 35 ⁇ 2°C: MRSA, PA01 , and S.
  • MIC values indicate that both Ga and Bi exert an antibacterial effect against various bacterial species, although the effect varies for different species. Variation in MIC values for B1CI3 against MRSA and PA01 was probably caused by inadequate dissolution of the B1CI3 (high values indicating that the salt was not completely dissolved and was thus unavailable for inhibition). b) Inhibition of bacterial growth using film contact method
  • a film contact method (Yasuyuki et al, 2010) was used. Streak plates of Pseudomonas aeruginosa (PA01 ) were made and 1 colony was inoculated to 5 ml tryptic soy broth (TSB) in culture tubes and grown under shaking conditions for 18 hours. Cell density was measured in a spectrophotometer at OD 600 nm and counted using a cell counting chamber. The cell culture was adjusted with sterile TSB to 1 -5 X 10 6 cells/ml.
  • Specimens of commercially pure (cp) titanium coins (0 6.25 mm) and cp titanium coins with coatings of TiBi, TiNBi, TiGa or TiNGa were aseptically prepared and put in respective well of a 12 well plate. Thin transparent plastic film was punched, and sterilized using 70 % ethanol and UV irradiation on each side. A 15 ⁇ drop of bacteria in TSB was applied on each specimen. One thin plastic film per specimen was placed over the bacteria on the specimens so that the bacterial solution was evenly spread over the specimen surface, ensuring good contact.
  • the film of each specimen was aseptically removed and washed by pipetting 1 ml PBS over the surface into a separate 2 ml eppendorf tube per specimen.
  • the specimens were transferred to the same eppendorf tubes as used when washing the film.
  • First each specimen surface was washed by pipetting the very same PBS as the film was previously washed with.
  • the specimens were sonicated and for 1 minute and vigorously vortexed for 1 minute in the very same tube as previously used when washing the film.
  • TiBi, TiNBi, TiGa, TiNGa All surface coatings (TiBi, TiNBi, TiGa, TiNGa) were found to enhance fibroblast mitochondrial activity, i.e. cell viability, compared to uncoated titanium surfaces, using a cytotoxicity test.
  • Cytotoxicity was assessed with a (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay using human fibroblasts (MRC-5).
  • MTS assay measures the mitochondrial activity in cells and correlates to the viability / the number of cells.
  • specimens of commercially pure (cp) titanium, TiBi coated titanium, TiNBi coated titanium, TiGa coated titanium and TiNGa coated titanium produced as described in Example 2A were used.
  • the cells were subcultured according to guidelines from the American Type Culture Collection. They had reached approximately 80 % confluence when they were used in the experiment.
  • Six coins of each specimen were aseptically placer in a 24 well plate, 1 coin per well.
  • 100 ⁇ of MRC-5 cells at 1 x10 5 cells/ml were added to each disc and controls. The plates were then incubated for one hour to allow cell attachment before 1 ml complete cell culture media was added to each well. The plates were then incubated for 24 hours before analysis.
  • For the MTS assay 4 coins of each specimen were transferred from the 24 well plates to 48 well plates. 500 ⁇ MTS assay reagent was added to each well and were incubated for 4 hours. Absorbance was then read at 490 nm. The absorbance values for each specimen were normalized to the uncoated titanium control in percentage set to 100 % (Table 13).
  • DAPI is a fluorescent stain that binds to cell nucleus and can thus be used to visualize cells on metals.
  • Table 13 Mitochondrial activity (i.e. viability) as measured with an MTS assay for human fibroblasts cultured on uncoated and coated titanium specimens.
  • a surface layer comprising a compound of a post-transition metal here a compound of gallium, bismuth, or both
  • a biocompatible metal substrate titanium
  • post-transition metal here a compound of gallium, bismuth, or both
  • acidic conditions which may occur very locally in the tissue in the case of inflammation/infection, the release of post-transition metal may even be significantly increased.
  • the tested surface layers are non-toxic to human fibroblast cells and may in fact enhance fibroblast mitochondrial activity.

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Abstract

L'invention concerne un dispositif médical destiné à entrer en contact avec un tissu vivant, comprenant un substrat présentant une surface, laquelle surface comprend une couche contenant un ou plusieurs composés d'au moins un métal post-transition non toxique, tel qu'un composé de gallium ou de bismuth. Il s'avère qu'une couche contenant au moins un métal post-transition non toxique inhibe la formation de biofilm sur la surface du dispositif médical, ce qui permet de réduire le risque d'infection par exemple autour d'un implant dentaire. Un procédé de production du dispositif médical comprend : a) la fourniture d'un substrat ayant une surface ; et l'application d'un composé d'au moins un métal post-transition non toxique sur ladite surface pour former une couche, par exemple à l'aide d'une technique de dépôt de film mince.
EP13709112.0A 2012-03-30 2013-03-13 Dispositif médical présentant une surface comprenant un métal antimicrobien Pending EP2830672A1 (fr)

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EP13709112.0A EP2830672A1 (fr) 2012-03-30 2013-03-13 Dispositif médical présentant une surface comprenant un métal antimicrobien

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US201261617940P 2012-03-30 2012-03-30
EP12162632 2012-03-30
EP13709112.0A EP2830672A1 (fr) 2012-03-30 2013-03-13 Dispositif médical présentant une surface comprenant un métal antimicrobien
PCT/EP2013/055184 WO2013143857A1 (fr) 2012-03-30 2013-03-13 Dispositif médical présentant une surface comprenant un métal antimicrobien

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EP2830672A1 true EP2830672A1 (fr) 2015-02-04

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EP13709112.0A Pending EP2830672A1 (fr) 2012-03-30 2013-03-13 Dispositif médical présentant une surface comprenant un métal antimicrobien
EP13714892.0A Active EP2830673B1 (fr) 2012-03-30 2013-03-27 Dispositif médical ayant une surface comprenant de l'oxyde de gallium

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EP13714892.0A Active EP2830673B1 (fr) 2012-03-30 2013-03-27 Dispositif médical ayant une surface comprenant de l'oxyde de gallium

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US (1) US20130266629A1 (fr)
EP (2) EP2830672A1 (fr)
JP (2) JP6293725B2 (fr)
KR (3) KR20140139058A (fr)
CN (3) CN104519920A (fr)
AU (2) AU2013242166B2 (fr)
CA (2) CA2867787C (fr)
IN (2) IN2014DN07736A (fr)
RU (2) RU2651463C1 (fr)
WO (2) WO2013143857A1 (fr)

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CN104519920A (zh) 2015-04-15
EP2830673B1 (fr) 2021-06-23
IN2014DN07735A (fr) 2015-05-15
AU2013242166A1 (en) 2014-10-02
WO2013144185A1 (fr) 2013-10-03
KR20210038996A (ko) 2021-04-08
CN107899076B (zh) 2021-07-23
CA2867787A1 (fr) 2013-10-03
RU2636515C1 (ru) 2017-11-23
CA2867787C (fr) 2022-01-04
CA2867761C (fr) 2020-07-07
KR20140139058A (ko) 2014-12-04
IN2014DN07736A (fr) 2015-05-15
JP6293725B2 (ja) 2018-03-14
EP2830673A1 (fr) 2015-02-04
AU2013241859A1 (en) 2014-10-09
AU2013242166B2 (en) 2016-05-05
KR20140140600A (ko) 2014-12-09
JP2015516829A (ja) 2015-06-18
CN104203294A (zh) 2014-12-10
CN107899076A (zh) 2018-04-13
AU2013241859B2 (en) 2016-09-22
US20130266629A1 (en) 2013-10-10
KR102380545B1 (ko) 2022-03-30
CA2867761A1 (fr) 2013-10-03
WO2013143857A1 (fr) 2013-10-03
RU2651463C1 (ru) 2018-04-19
JP2015518387A (ja) 2015-07-02

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